The invention relates to the delivery of a composition to the liver.
The liver is one of the largest visceral organ in the body; in the average adult man, the liver weighs about 1.5 kilograms. The basic functions of this multi-functional organ can be divided into three groups: vascular functions for the storage and filtration of blood; a secretory function for the secretion of bile into the gastrointestinal tract; and metabolic functions concerned with the majority of the metabolic systems of the body.
The liver receives its blood supply from two major sources, the portal vein and the hepatic artery. The schematic representation of the liver shown in FIG. 1 depicts the major vessels of the liver. Note that the hepatic artery and portal vein supply blood to the liver, while the hepatic vein, which drains into the vena cava, removes blood from the liver.
About 1100 mL of portal blood enters the liver each minute via the portal vein. The portal vein is generally formed by the convergence of the splenic and superior mesenteric veins. In addition to the portal blood flow, approximately 350 mL of blood flows into the liver each minute through the hepatic artery. The portal blood flow is controlled by the various factors that determine flow through the gastrointestinal tract and the spleen.
The hepatic vein drains into the inferior vena cava, which contacts and is partly surrounded by the posterior surface of the liver. At any point in time, the normal blood volume of the liver, including the blood in the hepatic vein and the hepatic sinuses, is about 500 mL. Because the liver is an expandable and compressible organ, the liver can additionally store or release large quantities of blood. For example, when high pressure in the right atrium causes back pressure in the liver, the liver expands, and as much as 1 L of extra blood may be stored in the hepatic veins and sinuses. Likewise, in times of diminished blood volume, the liver may compress, thereby releasing extra blood into the circulatory system.
There are many diseases associated with the liver which affect one or more of the organ""s functions. These diseases include hepatitis, cancer, cirrhosis, biliary atresia, cholestasis, and fatty liver. A process for facilitating delivery of a composition (e.g., a drug) to the liver would be useful in treating, or at least alleviating the symptoms of, a disease of the liver.
In general, the invention features a method and apparatus for facilitating delivery of a composition to the liver via a non-surgical percutaneous approach that utilizes the portal vein.
In a first aspect, the invention features a method for delivering a composition to a liver via the portal vein that includes the steps of: (a) inserting a first catheter into the portal vein via a non-surgical percutaneous route, wherein the first catheter includes a deployable means (e.g., a balloon) for occluding the portal vein; (b) inserting a second catheter into a blood vessel draining the liver, wherein the second catheter includes a deployable means (e.g., a balloon) for occluding the blood vessel draining the liver; and (c) delivering the composition to the liver via a delivery catheter that is either the first catheter or the second catheter.
In one embodiment of the first aspect of the invention, the composition delivered to the liver by the delivery catheter is collected by a collecting catheter that is either the first catheter or the second catheter, wherein the delivery catheter and the collecting catheter are different. In another embodiment, the delivery catheter is connected to the collecting catheter, such that the composition collected by the collecting catheter is returned to the liver by the delivery catheter.
In other embodiments of the first aspect of the invention, at least one of the first catheter and the second catheter is adapted for insertion via a conventional introducer sheathe, is adapted for insertion over a guidewire, is equipped with a gauge for monitoring pressure, is equipped with a flow meter for monitoring flow rate, or is at least in part radio-opaque.
In a second aspect, the invention features a method for delivering a composition to a liver via the portal vein that includes the steps of: (a) inserting a first catheter into the portal vein via a non-surgical percutaneous route, wherein the first catheter includes a deployable means (e.g., a balloon) for occluding the portal vein; (b) inserting a second catheter into a blood vessel draining the liver, wherein the second catheter includes a deployable means (e.g., a balloon) for occluding the blood vessel draining the liver; (c) inserting, into a blood vessel, other than the portal vein, supplying the liver, a third catheter that includes a deployable means (e.g., a balloon) for occluding the blood vessel, other than the portal vein, supplying the liver; and (d) delivering the composition to the liver via a delivery catheter that is either the first catheter, the second catheter, the third catheter, the first and the second catheters, the first and the third catheters, or the second and the third catheters, wherein the composition delivered to the liver by the delivery catheter is collected by a collecting catheter that is either the first catheter, the second catheter, the third catheter, the first and the second catheter, the second and the third catheter, or the first and the third catheter, and wherein the delivery catheter and the collecting catheter are different.
In one embodiment of the second aspect of the invention, at least part of the delivery catheter is connected to at least part of the collecting catheter, such that the composition collected by the collecting catheter is returned to the liver by the delivery catheter. In another embodiment, the blood vessel, other than the portal vein, supplying the liver is the hepatic artery. In other embodiments of the second aspect of the invention, at least one of the first catheter, the second catheter, and the third catheter is adapted for insertion via a conventional introducer sheathe, is adapted for insertion over a guidewire, is equipped with a gauge for monitoring pressure; is equipped with a flow meter for monitoring flow rate, or is at least in part radio-opaque.
In another embodiment of the first and second aspect of the invention, the first catheter includes a means (e.g., a port that is in communication with a lumen) for collecting blood flowing into the portal vein. In another embodiment, the means for collecting blood flowing into the portal vein of the first catheter is connected to a fourth catheter, which may be inserted into a blood vessel that does not supply the liver and may include a means (e.g., a port that is in communication with a lumen) for delivering blood into the blood vessel that does not supply the liver. In yet another embodiment, the first catheter includes a port that is proximal to the deployable means for occluding the portal vein of the first catheter.
In other embodiments of the first and second aspect of the invention, the blood vessel draining the liver is the hepatic vein, and the second catheter may further include a port that is distal to the deployable means for occluding the hepatic vein of the second catheter. In other embodiments, the blood vessel draining the liver is the vena cava, and the second catheter may further include a second, different deployable means for occluding the vena cava and a port located between each of the deployable means for occluding the vena cava of the second catheter, and the second catheter may further include a means for allowing continuous blood flow through the vena cava, such as a means that includes a first port located distal to both of the deployable means for occluding the vena cava of the second catheter, a second port located proximal to both of the deployable means for occluding the vena cava of the second catheter, and a lumen that allows communication between the first port and the second port.
In various other embodiments of the first and second aspects of the invention, the non-surgical percutaneous route is visualized by ultrasound guidance, is visualized by radiographic guidance, is visualized by magnetic resonance guidance, is an intravenous intrahepatic approach, or is a transcutaneous transhepatic approach.
In a third aspect, the invention features a method for delivering a drug to a liver that utilizes the portal vein that includes the steps of: (a) inserting a catheter into the portal vein via a non-surgical percutaneous route, wherein the catheter includes a deployable means (e.g., a balloon) for occluding the portal vein; and (b) delivering the drug to the liver via the catheter.
In various embodiments of the third aspect of the invention, the non-surgical percutaneous route is visualized by ultrasound guidance, is visualized by radiographic guidance, is visualized by magnetic resonance guidance, is an intravenous intrahepatic approach, or is a transcutaneous transhepatic approach. In other embodiments, the catheter is adapted for insertion via a conventional introducer sheathe, is adapted for insertion over a guidewire, is equipped with a gauge for monitoring pressure, is equipped with a flow meter for monitoring flow rate, or is at least in part radio-opaque.
By xe2x80x9cdrugxe2x80x9d is meant a compound or composition that acts as a therapeutic, diagnostic, or preventive agent on a liver cell. A drug may produce a metabolic or phenotypic change in a liver cell, may alter the growth of a liver cell, may influence a liver cell""s interactions with other cells, may influence the genetic make-up or genetic activity of a liver cell, or may result in the death of a liver cell. For the purposes of the invention, a drug specifically excludes any compound or composition administered at a dosage or delivered at a concentration sufficient to either impede blood flow through the hepatic vasculature (e.g., ethanol or other embolization agents) or facilitate blood flow though the hepatic vasculature (e.g., heparin).
By xe2x80x9cliver cellxe2x80x9d is meant a cell that is located in the liver. Liver cells include, without limitation, cancerous liver cells hepatocytes, Kupffer cells, Ito cells, endothelial cells lining the hepatic sinusoids, vascular endothelial cells lining the hepatic blood vessels, and any cells of any origin which happen to reside in the liver (e.g., metastatic cancer cells of ectopic origin).
By xe2x80x9cproximalxe2x80x9d is meant that a catheter feature is closer to the person administering the catheter than a reference object. For example, a feature (e.g., a port) located proximal to a reference object (e.g., an occluding device) is closer to the person administering the catheter than the reference object. Hence, the feature is located between the person administering the catheter and the reference object.
By xe2x80x9cdistalxe2x80x9d is meant that a catheter feature is more distant from the person administering the catheter than a reference object. For example, a feature (e.g., a port) located distal to a reference object (e.g., an occluding device) is farther from the person administering the catheter than the reference object. Hence, the reference object is located between the person administering the catheter and the feature.
The invention described herein provides methods for delivering a composition to the liver via the portal vein by using a non-surgical, percutaneous approach. The invention also features method for the liver-specific delivery of a composition. By localizing the delivery of a composition to the liver, a higher concentration of a composition (e.g., a drug) may be administered than would have been administered systemically due to, for example, toxicity of the composition to other areas of the body (e.g., the bone marrow compartment).